In developmental and epileptic encephalopathies (DEEs), the seizure phenotype is rarely static. Infantile epileptic spasms typically subside and are often replaced years later by other seizure types, and in several genetically defined DEEs seizure-free intervals precede seizure recurrence. Although these transitions are linked to long-term outcome, little is known about the molecular and cellular events that accompany them, because the interval is clinically silent and brain tissue is inaccessible. Animal studies have only partly filled this gap: most DEE models have been characterized at a single age, and models with continuous seizures provide no interval to investigate. We recently performed time-resolved deep phenotyping of Cyfip2+/R87C mice, which recapitulate neonatal seizure-like events, a prolonged seizure-free interval, and adult-onset spontaneous recurrent seizures with premature death, using transcriptomic, ultrastructural, proteomic, and lipidomic analyses across four postnatal stages. Here we summarize the temporal landscape: excitatory synapse number falls while remaining synapses relocate to dendritic shafts, oligodendrocyte-lineage cells, microglia, and astrocytes are engaged sequentially, and lipid droplets accumulate progressively in astrocytes. We also highlight what remains unresolved. The highest-resolution analyses were performed only after seizure recurrence, illustrating a tradeoff between analytical depth and temporal coverage, so the juvenile interval preceding recurrence remains the central knowledge gap. Even so, the emerging picture is that the seizure-free interval is not a period of quiescence but one of active neuron-glia and metabolic remodeling. Defining this interval more precisely, and identifying biomarkers for patient staging, may transform a clinically silent phase into a well-defined therapeutic window for stage-specific intervention.

Plasticity within somatosensory circuits enables adaptations to environmental changes, however these can become maladaptive following injury and lead to chronic pain states. Presynaptic neurexins (Nrxns) are key organizers of synapse function that bind to a wide variety of postsynaptic proteins in a splice-isoform dependent manner to regulate synaptic connectivity, transmission and plasticity. Here we observed that NRXN alternative splicing at splice site 4 (SS4), an exon critical for synaptic function and long-term potentiation at synapses in the central nervous system, is plastic in human sensory neurons of the dorsal root ganglia (DRG). Taking a reverse translational approach, we used mouse models to understand what might regulate these splicing changes in DRG. We observed a shift to transcripts lacking this alternatively spliced exon for Nrxn1 and Nrxn3 in response to depolarization, but not sensitization with PGE 2 . Alternative splicing at SS4 was not altered by acute inflammatory pain but was reduced by central axotomy in vivo . We found that Nrxn alternative splicing patterns in DRG are dynamic during nervous system development, and vary between neurons of the DRG, spinal cord, and cortex in adult animals. Lastly, we observed that exon use at this site is conserved between species for Nrxn1α, but significantly different for all other isoforms. Thus, Nrxn alternative splicing at SS4 is plastic in human and mouse DRG neurons, which may influence somatosensory circuit wiring and synaptic function.

Sleep is a fundamental regulator of brain homeostasis, yet how distinct brain cell types contribute to this process remains poorly understood. Microglia, the resident immune cells of the central nervous system, actively regulate neuroinflammatory tone, metabolic waste clearance, and synaptic remodeling, thereby contributing to neural circuit maintenance and proteostasis. Delineating the different functions played by microglia during specific brain states, such as sleep, represents an active area of research. In this article, we review a growing literature supporting the notion that sleep dynamically shapes microglial functional outputs. We further suggest that the failure of the sleep-microglia axis may represent an important component of the molecular framework of Alzheimer's disease (AD), contributing to disease progression. Finally, we discuss preclinical and clinical evidence suggesting that sleep-targeting interventions may modulate AD pathology, and highlight the possibility that restoring sleep physiology could recalibrate microglial homeostatic functions and slow disease progression.

The KOLF2.1J human induced pluripotent stem cell (iPSC) line was created as a reference for neurological disease modeling. Previous genotyping efforts identified several large structural variants (SVs), raising questions about their potential impact on neuronal differentiation. Here, we identified 37 additional SVs using long-read sequencing and optical genome mapping. Additionally, we found that one of the known SVs contained a previously undetected overlap with RYBP, a neurodevelopmental gene. To assess the functional consequences of these SVs, we performed single-cell RNA sequencing of day 90 forebrain organoids derived from KOLF2.1J and two independent control iPSC lines. While cell-type composition was preserved, multiple SV-affected genes were differentially expressed and cell-cell adhesion and synapse-related processes were enriched in KOLF2.1J organoids. These findings highlight the importance of robust genetic characterization and multi-line validation for reliable iPSC-based modeling.

Alcohol abuse is the primary risk factor for alcohol use disorder (AUD), a leading cause of preventable morbidity and mortality worldwide. While direct effects of alcohol on neuronal function are well established, the role of microglia in acute and chronic neurological dysfunction in AUD remains underappreciated. Using mouse models of binge and high-intensity alcohol exposure and longitudinal in vivo imaging, we found that microglia exhibited acute and progressive morphological responses that preceded but paralleled ethanol-induced sedation. Ethanol also induced microglia-dependent extracellular matrix (ECM) disruption, synapse elimination, and reduced neuronal activity and density. Genetic deletion of microglial Myd88 protected against ethanol-induced microglial reactivity, neuronal damage and dysfunction, intoxication, and motor impairments by preventing ECM disruption. Frontal cortex ECM was similarly disrupted in human brain tissue from individuals with AUD. These findings identify microglia as cellular drivers of brain dysfunction following alcohol abuse and MyD88 as a critical therapeutic target for AUD.

Optoelectronic synaptic devices based on 2D van der Waals (vdW) materials are very promising for next-generation, energy-efficient data processing and sensing; however, flake-based fabrication limits their practical application. Here, scalable inductively coupled plasma-sulfurized nanocrystalline MoS2 (nc-MoS2) and graphene heterostructure have been investigated for optoelectronic synaptic device applications. The nc-MoS2 with abundant sulfur vacancies, grain boundaries, and defect states facilitates charge trapping at the nc-MoS2/Graphene interface and introduces negative persistent photocurrent (PPC). The PPC state is effective only for ultraviolet (UV) light because of the high recombination of photogenerated charge carriers at the defect sites of nc-MoS2 for higher wavelength light; however, it enables energy-efficient, neuromorphic UV-selective sensing that could serve as a UV exposure alert system. The device demonstrates efficient emulation of fundamental synaptic behaviors, including short-term memory, long-term memory, and paired-pulse facilitation, through modulation of optical stimuli such as light intensity and illumination duration, as well as reconfiguration via the gate voltage. A 96.94% accuracy in MINST image recognition has also been demonstrated through deep neural network-based simulation, which seems potentially applicable in neuromorphic computing. Thus, the nc-MoS2/Gr heterostructure, as a scalable, 2D vdW system, has significant potential for optoelectronic synapses.

Defective synaptic transmission is a prominent pathology that underlies cognitive deficits in Alzheimer's disease (AD), highlighting the need to elucidate molecular mechanisms of synaptic failure. Vacuolar H+-ATPase (V-ATPase), a proton-pumping enzyme, is essential for synaptic vesicle acidification and neurotransmitter loading. However, whether SV-associated V-ATPase is vulnerable to AD remains unclear. Here, using SV-rich fractions from postmortem brain tissues, we identified SV-associated V-ATPase deficits, including decreased enzymatic activity, impaired complex assembly, and altered expression of its key subunits in AD. SV-associated V-ATPase dysfunction was further associated with pathological and clinical characteristics of AD. Genetic downregulation of the V-ATPase V1D subunit, a component reduced in AD brains, disrupted V-ATPase proton transport and impaired SV acidification. Further experiments using 5×FAD mice, which exhibited AD-like SV-associated V-ATPase deficits, demonstrated the deleterious impact of V-ATPase dysfunction on SV acidification and synaptic transmission including presynaptic neurotransmitter release. In addition, ex vivo studies identified amyloid β-induced oxidative stress as a driver of V1D loss and V-ATPase disassembly, linking AD pathology to SV-associated V-ATPase dysfunction. These findings indicate that SV-associated V-ATPase dysfunction contributes to synaptic failure and cognitive deficits in AD. Therapeutic avenues to mitigate V-ATPase dysfunction have the potential to attenuate synaptic failure for the management of AD.

α-Synuclein is a presynaptic protein that has been extensively studied for its role in Parkinson's disease. Multiplication and missense variants in the gene encoding α-synuclein are causes of familial PD, and aggregated α-synuclein is a major component of Lewy bodies and Lewy neurites, the histopathological hallmark of the disease. However, the native function of α-synuclein remains unclear, though several lines of evidence suggest it modulates presynaptic function. α-Synuclein binds the vesicular SNARE protein synaptobrevin-2/VAMP2, and increased levels of α-synuclein potentiate SNARE complex levels without impacting exocytic rate. Given the essential role of synaptobrevin-2 in synaptic function we sought to examine how increased expression of α-synuclein, at levels observed in familial synucleinopathies with SNCA triplication, impacts the trafficking of this essential SNARE protein. Modest (approximately 2-fold) overexpression of α-synuclein in cultured murine hippocampal neurons caused a slowing in the endocytic retrieval of synaptobrevin-2, without impacting either the targeting of the protein to synapses or altering endocytosis. We also show that α-synuclein is not working antagonistically with the synaptobrevin-2 chaperone synaptophysin, and likely acts at least partially via direct binding to synaptobrevin-2. Finally, increased expression of α-synuclein induces synaptic depression upon repeated neuronal depolarisation, in a manner requiring binding to synaptobrevin-2. We reveal α-synuclein as a modulator of synaptobrevin-2 endocytic trafficking and highlight perturbed SNARE protein trafficking as a potential contributor to synaptic dysfunction and neuronal health in Parkinson's disease.

Neurons rely on tightly coordinated mechanisms of protein synthesis and degradation to maintain cellular homeostasis, a process known as proteostasis. Given their highly polarised and compartmentalised nature, regulation of proteostasis is especially important at neuronal synapses, which are spatially distant from the soma yet require rapid on-demand adaptation of the synaptic proteome. Neurons meet their demand for synaptic proteostasis through localised mRNA transport and translation, alongside specialised pathways for protein degradation. Recent advances reveal that thousands of transcripts localise to distal neuronal compartments and that their distribution may be shaped by RNA stability, RNA dynamics, and organelle-hitchhiking transport mechanisms. In parallel, processes such as synaptic autophagy and endolysosomal trafficking are crucial for maintaining synaptic structure and neurotransmission. Disruptions in these finely balanced mechanisms are a common underlying feature of various neurological disorders, including fragile X syndrome, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. This overview highlights key milestones and remaining questions in synaptic proteostasis, focusing on how local protein synthesis and degradation work together to preserve synaptic integrity and how their dysregulation can lead to disease.

With the rapid growth of artificial intelligence, conventional von Neumann architectures face increasing limitations arising from memory-processor separation, high data-transfer latency, and power consumption. Memristive devices offer a promising route towards in-memory and neuromorphic computing by combining information storage and processing within compact two-terminal structures. Among emerging memristive technologies, electro-optical memristors are particularly important because they integrate electrical programmability with optical modulation, enabling high-bandwidth, parallel, and energy-efficient signal processing. Unlike purely electrical memristors, which are often limited by interconnect bottlenecks, switching variability, and bandwidth constraints, electro-optical memristors provide additional degrees of freedom through light intensity, wavelength, pulse duration, and timing. Compared with purely optical memory elements, they offer nonvolatile or tunable electrical conductance states that can be directly interfaced with electronic circuits. This review critically summarizes the evolution from conventional resistive-switching memristors to optical and electro-optical memristive systems, with emphasis on material platforms, switching mechanisms, device architectures, synaptic and neuronal functionalities, and system-level integration. Particular attention is given to electro-optical memristors for optoelectronic synapses, in-sensor computing, photonic neuromorphic processing, and brain-inspired hardware. Finally, the key challenges, including device variability, endurance, optical/electrical integration, scalability, and commercialization, are discussed together with future perspectives for next-generation electro-optical neuromorphic computing.

Autism spectrum disorder (ASD) presents a significant therapeutic challenge due to limited treatment options. While non-pharmacological approaches based on sensory stimulation have shown promise in clinical practice, the underlying mechanisms remain poorly understood. This study explored the therapeutic potential of tactile experience enrichment (TEE) during specific developmental windows in Shank3 KO mice, a model of ASD. We found that pre-weaning TEE robustly rescued core behavioral deficits, including social interaction and repetitive grooming, whereas juvenile TEE only improved social behavior. RNA sequencing of the anterior cingulate cortex (ACC) and dorsolateral striatum (DLS) revealed TEE-induced alterations in synaptic gene expression, including the upregulation of the Polo-like kinase 1 (PLK-1) pathway, which may modulate synaptic maturation. Furthermore, pre-weaning TEE restored dendritic spine density and morphology, along with synaptic transmission, in both the ACC and DLS. These findings indicate that early tactile enrichment, particularly during the pre-weaning period, can effectively alleviate core ASD-related behaviors in Shank3 KO mice by modulating synaptic structure and function, highlighting its potential as a therapeutic intervention for ASD.

Background Thromboembolic complications are common in patients with pancreatic cancer, with up to 20% of patients developing venous thromboembolism. While hypercoagulation in pancreatic cancer has been widely studied, fibrinolysis is less well characterized. Plasmin generation (PG) is a novel approach to assess fibrinolytic activity and may provide new insights into thrombotic risk in this population. This study aimed to compare the PG profile of patients with pancreatic cancer with that of healthy individuals. Methods This single-center cohort study included patients with advanced pancreatic cancer initiating chemotherapy at the Maastricht University Medical Center between 2022 and 2023. Plasma samples were obtained before chemotherapy ( t 0 ) and 8 weeks later ( t 8 ). PG and thrombin generation (TG) were measured; TG/PG ratios were calculated to evaluate the balance between coagulation and fibrinolysis. Thromboembolic events were recorded for 6 months. Results In total, 18 patients with pancreatic cancer and 18 healthy subjects were included. At baseline, patients showed higher endogenous plasmin potential levels compared with controls, whereas PG remained elevated at t 8 despite chemotherapy. PG lag time was prolonged in patients at t 8 . Patients showed lower TG/PG ratios for endogenous thrombin/plasmin potential. Five patients (28%) developed thromboembolic events. Although PG parameters were not associated with thromboembolic events, patients who developed thromboembolic events showed lower TG/PG potential ratios. Conclusion Patients with pancreatic cancer exhibited a disbalance in their PG profile, with a delayed but increased capacity to generate plasmin. Future studies are required to assess whether PG associates with thromboembolic disease and survival.